Introduction Targeted screening methods that cover a broad range of common drugs and drugs of abuse are essential for forensic laboratories. The most common techniques used are immunoassay techniques, GC-MS, and more recently LC-MS(MS). The major advantages of immunoassay techniques are their easy use and fast turnaround time, however, mass spectrometric techniques are more selective and/or sensitive, and technically more demanding. The aim of this study was to develop a LC-MS/MS based screening technique that covers the most common drugs observed in forensic analysis, using fast extraction method combined with fully automated data processing. Methods After liquid-liquid extraction (LLE) of 100 μL of post-mortem blood, 105 of the most common drugs and drugs of abuse were separated using a Shimadzu Prominence HPLC system with an C18 separation column (Eclipse XBD C18, 4.6 × 150 mm, 5 μm), using gradient elution with a mobile phase of 50 mM ammonium formate buffer pH 3.5 / acetonitrile. The drugs were detected using an Applied Biosystems 3200 Q-TRAP LC-MS-MS system (ESI, MRM mode). The method was fully validated according to international guidelines. Quantification data obtained using calibration curves were compared to a one point calibration. Results The assay was found to be selective for the compounds of interest. The calibration range spanned from therapeutic to potentially toxic concentrations described for these drugs. With a few exceptions, recoveries were typically > 70%. Accuracy, repeatability and intermediate precision were within the required limits for most analytes. Using a one point calibration, most analytes obtained similar accuracy and precision compared to a full calibration. Data processing was automated based on custom built settings. All quantifier transition peaks matching the retention times within 2% maximum difference that resulted in a calculated concentration above the lowest calibrator were reported as tentatively positive for further checking. In the scenario where the qualifier ion matched the MRM ratio obtained from in batch quality control samples within the EU mass spectrometry guidelines, the drug was highlighted in green. In the scenario where the MRM ratio did not match, the drug was still shown as tentatively positive, but highlighted in yellow. Peak review including MRM ratio was assessed for all tentatively positive peaks. Conclusions The presented LC-MS-MS assay has proven to be applicable for determination of the studied analytes in blood. The fast and reliable extraction method combined with automated processing gives the opportunity for overnight turnaround times. The method has been applied to routine analysis at the Victorian Institute of Forensic Medicine since April 2009 and approximately 3500 blood samples have been analysed.